Principal Investigator/Program Director (Last, first, middle): Hansen, Laura, A RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3348-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 7587-Project_summary-abstract.pdf Mime Type: application/pdf 7. * Project Narrative 1005-project_narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 7032-Bib_and_ref_cited.pdf Mime Type: application/pdf 9. Facilities &Other Resources 4565-Facilities_and_other_resources.pdfMime Type: application/pdf 10. Equipment 4335-equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Hansen, Laura, A Project Summary-Abstract Exposure to the ultraviolet (UV) component of sunlight is the major cause of nonmelanoma skin cancer, the most common form of cancer in the United States. Despite its significance for human health, however, the mechanisms through which UV causes cancer are not well understood. One potential mechanism for skin carcinogenesis involves the UV-induced activation of Erbb2, a proto-oncogene and orphan receptor tyrosine kinase. Our preliminary data reveal novel mechanisms through which Erbb2 contributes to skin carcinogenesis at multiple stages, both during tumor development and progression. Our central hypotheses are 1) that Erbb2 promotes cell cycle progression and thus increases UV-induced skin carcinogenesis by dampening DNA damage response checkpoints and 2) that Erbb2's suppression of proteinase inhibitor Thrombospondin 1 and its upregulation of matrix metalloproteinases stimulate keratinocyte invasion and angiogenesis, leading to malignant progression. The long-term objective of this application is to understand the biological functions of Erbb2 during carcinogenesis and the mechanisms through which Erbb2 acts. Studies are proposed to reveal the biological significance of Erbb2 in skin tumor development and progression, to determine the molecular mechanisms by which Erbb2 regulates cell cycle progression and a DNA damage checkpoint through Cdc25a, and to determine how Erbb2 causes skin cancer progression. These studies will use models that we have developed for both the inhibition and genetic ablation of Erbb2 in the skin. Upon completion, these studies will reveal the basic mechanisms of cell cycle regulation and checkpoint control following UV exposure as well as novel mechanisms through which Erbb2 regulates cell cycle arrest after DNA damage and promotes malignant progression. This research will provide a comprehensive analysis of the importance of Erbb2 in skin carcinogenesis, will elucidate novel mechanisms through which Erbb2 acts, and will provide new targets for therapeutic intervention during skin carcinogenesis. Project Description Page 6